Trial Title:
A Randomized Secondary Adjuvant Treatment Intervention Study Comparing Trastuzumab-Deruxtecan to SOC Therapy in EBC Patients with Molecular Relapse
NCT ID:
NCT06643585
Condition:
Breast Cancer
Conditions: Official terms:
Recurrence
Trastuzumab
Trastuzumab deruxtecan
Study type:
Interventional
Study phase:
Phase 3
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Trastuzumab-Deruxtecan
Description:
Trastuzumab-Deruxtecan (i.v. 5,4 mg/kg, q3w) + endocrine therapy (if
hormonal-receptor-positive) for 16 cycles or until relapse, if earlier
Arm group label:
Arm A
Intervention type:
Other
Intervention name:
Physicians Choice (PhC).
Description:
Continuous treatment of physician's choice (may include endocrine treatment,
CDK4/6-Inhibition, T-DM1, Olaparib, Trastuzumab, Pertuzumab, Capecitabine or Neratinib)
Arm group label:
Arm B
Summary:
Prospective, multi-center, randomized, open label comparative Phase III study in patients
with intermediate to high-risk (as defined in the SURVIVE trial) HER2-positive or
HER2-low early breast cancer, who participate in the SURVIVE trial and experience a
molecular relapse, as assessed based on a positive circulating tumor DNA (ctDNA) result,
with 2:1 allocation to:
- Arm A: Trastuzumab-Deruxtecan (i.v. 5,4 mg/kg, q3w) + endocrine therapy (if
hormonal-receptor-positive) for 16 cycles or until relapse, if earlier
- Arm B: Continuous treatment of physician's choice (may include endocrine treatment,
CDK4/6-Inhibition, T-DM1, Olaparib, Trastuzumab, Pertuzumab, Capecitabine or
Neratinib)
Criteria for eligibility:
Criteria:
Inclusion Criteria:
Patients will be eligible for study participation if they comply with the following
criteria:
1. Written informed consent for all study procedures according to local regulatory
requirements prior to beginning specific protocol procedures.
2. Females or males, ≥ 18 years and ≤ 75 years of age.
3. Invasive breast carcinoma as revealed by local pathology that is either:
1. HER2-positive defined as an immunohistochemistry (IHC) score of 3+ and/or
positive by in situ hybridization (ISH) in Her2 2+ tumors (as defined in 2018
American Society of Clinical Oncology - College of American Pathologists
[ASCO-CAP] guidelines)
2. HER2-low defined as an immunohistochemistry (IHC) score of 1+ or an IHC score
of 2+ with a mandatory negative in situ hybridization (ISH), as defined in 2018
American Society of Clinical Oncology - College of American Pathologists
[ASCO-CAP] guidelines.
4. Complete resection of the tumor with resection margins free of invasive carcinoma
(R0).
5. Participation in the SURVIVE study and evidence of molecular relapse (as assessed
based on a positive ctDNA result obtained in the SURVIVE-study)
6. No evidence of metastatic relapse as revealed by a CT-scan (Abdomen/Chest) and a
SPECT bone scan that must be performed within 8 weeks before randomization (M0).
7. Completion of surgery, (neo-)adjuvant chemotherapy (if applicable) and radiation
therapy (if applicable, whichever occurred last) at least 6 months before
randomization.
8. Adjuvant/Postneoadjuvant treatment with Trastuzumab, Pertuzumab, T-DM1,
Capecitabine, Pembrolizumab, and Olaparib must be discontinued upon randomization
into Arm A (treatment with trastuzumab deruxtecan). The washout periods (see Table
2) must be complied with. Endocrine therapy (i.e. Tamoxifen, Letrozol, Anastrozol,
Fulvestrant or Exemestane) can be administered simultaneously to treatment with
trastuzumab deruxtecan.
9. Known HR status, per local laboratory assessment, as defined by ASCO-CAP guidelines
(≥1%): HR-positive status defined by either positive estrogen receptor (ER) and/or
positive progesterone receptor (PR) status. HR-negative status defined by both known
negative ER and known negative PR
10. Left ventricular ejection fraction (LVEF) ≥50% within 28 days prior to randomization
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at Screening
12. Adequate organ and bone marrow function within 28 days before randomization as
described in table 1. Organ and bone marrow function criteria must also be met when
laboratory tests are repeated within 3 days before Cycle 1 Day 1. Transfusion (red
blood cell or platelet) or G-CSF administration is not allowed within 2 weeks prior
to the day on which marrow function is assessed.
13. Adequate treatment washout period before treatment with trastuzumab deruxtecan (in
case of randomization into cohort A), defined in table 2.
14. Female subjects: Evidence of post-menopausal status or negative serum pregnancy test
for females of childbearing potential who are sexually active with a non-sterilized
male partner. For women of childbearing potential, a negative result for serum
pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be
available at the screening visit and urine beta-human chorionic gonadotropin (β-HCG)
pregnancy test prior to each administration of Investigational Medicinal Product
(IMP).
1. Women of childbearing potential are defined as those who are not surgically
sterile (underwent bilateral salpingectomy, bilateral oophorectomy, or complete
hysterectomy) or post-menopausal. Women will be considered post-menopausal if
they have been amenorrhoeic for 12 months without an alternative medical cause.
2. Female patients of childbearing potential who are sexually active with a
non-sterilized male partner must use at least one highly effective method of
contraception (see 5.5.1.) from the time of screening and must agree to
continue using such precautions for 7 months after the last dose of IMP. Not
all methods of contraception are highly effective. Female patients must refrain
from breastfeeding while on study and for 7 months after the last dose of IMP.
Complete heterosexual abstinence for the duration of the study and drug washout
period is an acceptable contraceptive method if it is line with the patient's
usual lifestyle (consideration must be made to the duration of the clinical
trial); however, periodic or occasional abstinence, the rhythm method, and the
withdrawal method are not acceptable.
3. Female subjects must not donate, or retrieve for their own use, ova from the
time of randomization and throughout the study treatment period, and for at
least 7 months after the final study drug administration. They should refrain
from breastfeeding throughout this time. Preservation of ova may be considered
prior to enrollment in this study.
15. Male subjects: Non-sterilized male patients who are sexually active with a female
partner of childbearing potential must use a condom with spermicide from screening
to 4 months after the final dose of IMP. Complete heterosexual abstinence for the
duration of the study and drug washout period is an acceptable contraceptive method
if it is in line with the patient's usual lifestyle (consideration must be made to
the duration of the clinical trial); however, periodic or occasional abstinence, the
rhythm method, and the withdrawal method are not acceptable. It is strongly
recommended for the female partners of a male patient to also use at least one
highly effective method of contraception throughout this period, as described in
section 5.5.1. In addition, male patients should refrain from fathering a child, or
freezing or donating sperm from the time of randomization/enrolment, throughout the
study and for 4 months after the last dose of IMP. Preservation of sperm should be
considered prior to enrolment in this study.
Exclusion Criteria:
1. Stage IV (metastatic) breast cancer.
2. Patients with a history of any secondary primary malignancy are ineligible with the
following exceptions:
- ipsi- or contralateral non-invasive carcinoma of the breast (DCIS)
- other, curatively treated in-situ disease
- adequately treated non-melanoma carcinoma of the skin
3. Prior treatment with T-DXd.
4. Combination of T-DXd with any other anti-cancer treatment is not permitted, except
for endocrine therapy.
5. Has substance abuse or any other medical conditions such as clinically significant
cardiac or psychological conditions, that may, in the opinion of the investigator,
interfere with the subject's participation in the clinical study or evaluation of
the clinical study results.
6. Patients with a medical history of myocardial infarction (MI) within 6 months before
first exposure to study intervention, symptomatic congestive heart failure (CHF)
(New York Heart Association Class II to IV), Subjects with troponin levels above ULN
at screening (as defined by the manufacturer), and without any myocardial related
symptoms, should have a cardiologic consultation before enrollment to rule out MI.
7. Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec
(males) based on average of the screening triplicate 12-lead ECG.
8. History of (non-infectious) Interstitial lung disease (ILD) / pneumonitis that
required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis
cannot be ruled out by imaging at screening.
9. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
10. Active primary immunodeficiency, known uncontrolled active HIV infection or active
hepatitis B or C infection. Patients positive for hepatitis C (HCV) antibody are
eligible only if polymerase chain reaction is negative for HCV RNA. Subjects should
be tested for HIV prior to randomization/enrolment if required by local regulations
or institutional review board (IRB)/ethics committee (EC).
11. Lung criteria:
1. Lung-specific intercurrent clinically significant illnesses including, but not
limited to, any underlying pulmonary disorder (for example pulmonary emboli
within three months of the study enrollment, severe asthma, severe COPD,
restrictive lung disease, pleural effusion etc.)
2. Any autoimmune, connective tissue or inflammatory disorders (for example
Rheumatoid arthritis, Sjogren's, sarcoidosis et cetera) where there is
documented, or a suspicion of pulmonary involvement at the time of screening.
Full details of the disorder should be recorded in the electronic case report
form (eCRF) for patients who are included in the study.
3. Prior pneumonectomy (complete)
12. Participants with past or resolved HBV infection are eligible only if they meet all
of the following criteria:
- HBsAg (-) (for > 6 months off anti-viral treatment),
- Anti-HBc (+) (IgG or total Ig),
- HBV DNA undetectable,
- Liver architecture normal (absence of any liver pathology including absence of
cirrhosis or fibrosis on prior imaging or biopsy,
- Absence of HCV co-infection or history of HCV co-infection.
- Access to a local Hepatitis B expert during and after the study. Such
participants should be closely monitored for HBV reactivation.
13. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral
vaccines are not considered attenuated live vaccines) within 30 days prior to the
first dose of T-DXd.
Note: Patients, if enrolled, should not receive live vaccine during the study and up
to 30 days after the last dose of IMP.
14. Has unresolved toxicities from previous anticancer therapy, defined as toxicities
(other than alopecia) not yet resolved to Grade ≤ 1 or baseline.
Note: Toxicities related to endocrine therapy should be documented but does not lead
to exclusion of patient from the study.
Also, subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as
no worsening to >Grade 2 for at least 3 months prior to first exposure to study
intervention and managed with standard of care treatment) that the investigator
deems related to previous anticancer therapy, such as:
1. Chemotherapy-induced neuropathy
2. Fatigue
3. Residual toxicities from prior immune-oncology treatment: Grade 1 or Grade 2
endocrinopathies which may include:
i. Hypothyroidism/hyperthyroidism ii. Type 1 diabetes iii. Hyperglycemia iv. Adrenal
insufficiency v. Adrenalitis vi. Skin hypopigmentation (vitiligo)
15. Known allergy or hypersensitivity to study treatment or any of the study drug
excipients.
16. History of severe hypersensitivity reactions to other monoclonal antibodies.
17. Pregnant or breastfeeding female patients, or patients who are planning to become
pregnant.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Start date:
December 1, 2024
Completion date:
December 1, 2031
Lead sponsor:
Agency:
Prof. Wolfgang Janni
Agency class:
Other
Source:
University of Ulm
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06643585
